Bottom Line:
The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group.The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group.Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.

ABSTRACTTo examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti-VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.

f2: Shift of the trabecular structural profile during osteonecrotic lesion repair in different groups.(A). Size distribution of trabecular bone of osteonecrotic lesion at 4-weeks post-administration in different groups. (B). Representative 3-D structure of trabecular bone of osteonecrotic lesion at 4-weeks post-administration in different groups. N = 7

Mentions:
For trabecular structure of osteonecrotic lesions by micro-CT measurement, there is no difference in quantities of either small-sized (0.036 ~ 0.2 mm) or large-sized (0.2 ~ 0.4 mm) trabecular bone between Anti-VEGF Group and Baseline Group. Compared to that at Baseline, less large-sized and more small-sized trabecular bones were found in Control Group and VEGF-Supplement Group, whereas more large-sized and less small-sized trabecular bone were found in Src-Inhibition Group and Supplement & Inhibition Group. Apparently, the size distribution of the trabeculae shifted toward thinning in the Control Group when compared to the baseline, and it further shifted toward thinning in the VEGF-Supplement Group when compared to the Control Group, whereas it hardly shifted in the Anti-VEGF Group or shifted toward moderately thickening in Src-Inhibition Group and Supplement & Inhibition Group when compared to the baseline. (Figure 2)

f2: Shift of the trabecular structural profile during osteonecrotic lesion repair in different groups.(A). Size distribution of trabecular bone of osteonecrotic lesion at 4-weeks post-administration in different groups. (B). Representative 3-D structure of trabecular bone of osteonecrotic lesion at 4-weeks post-administration in different groups. N = 7

Mentions:
For trabecular structure of osteonecrotic lesions by micro-CT measurement, there is no difference in quantities of either small-sized (0.036 ~ 0.2 mm) or large-sized (0.2 ~ 0.4 mm) trabecular bone between Anti-VEGF Group and Baseline Group. Compared to that at Baseline, less large-sized and more small-sized trabecular bones were found in Control Group and VEGF-Supplement Group, whereas more large-sized and less small-sized trabecular bone were found in Src-Inhibition Group and Supplement & Inhibition Group. Apparently, the size distribution of the trabeculae shifted toward thinning in the Control Group when compared to the baseline, and it further shifted toward thinning in the VEGF-Supplement Group when compared to the Control Group, whereas it hardly shifted in the Anti-VEGF Group or shifted toward moderately thickening in Src-Inhibition Group and Supplement & Inhibition Group when compared to the baseline. (Figure 2)

Bottom Line:
The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group.The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group.Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.

ABSTRACTTo examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti-VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.